Certain kinases that belong to the serine/threonine kinase family are located intracellularly and are involved in the transmission of biochemical signals such as those that affect cell proliferation and survival. One such serine/threonine kinase is PDK1, which is a regulator of at least 23 protein kinases that belong to the AGC kinase family (cAMP-dependent, cGMP-dependent, and protein kinase C). Signal transduction pathways downstream of PDK1 include the serine/threonine kinases protein kinase B (PKB/Akt), p70 ribosomal S6 kinase (p70S6K1), serum- and glucocorticoid-induced protein kinase (SGK), p90 ribosomal S6 kinase (RSK), and protein kinase C (PKC). Peifer et al., ChemMed Chem 3, 1810-1838 (2008).
The binding of growth factors to the cell surface receptors activates phosphoinositide-3 kinase (PI3K), which phosphorylates the substrate, phosphoinositidylinositol-4,5-triphosphate (PIP2) to form the second messenger, phosphoinositidylinositol-3,4,5-triphosphate (PIP3). PIP3 binds to both PDK1 and PKB/Akt, which are believed to co-localize at the cell membrane as a consequence. In addition to its interaction with PKB/Akt, PDK1 also phosphorylates and activates p70S6K1, SGK, RSK and PKC, which influences cell growth, proliferation, and survival, and regulates metabolism. Bayascas, J. R., Cell Cycle, 7, 2978-2982 (2008).
Cancer cells of common human tumor types, including breast, lung, gastric, prostate, haemotological and ovarian cancers, have gene mutations that result in abnormally high levels of PIP3. High levels of PIP3 cause overstimulation of PDK1 which result in constitutive activation the members of the AGC kinase family. As a consequence, tumor cell proliferation, reduced apoptosis and angiogenesis occur. In addition, cells lacking functioning PTEN, a lipid phosphatase that reduces cellular PIP3, are associated with a variety of human tumours including breast, prostate, endometrial cancers along with melanomas and glioblastomas. Steck et al., Nat. Genetics, 15, 356-362 (1997).
PDK1 function is critical to downstream signaling that results from activation of cells by growth factors because PKB/Akt, p70S6K, and RSK cannot be activated in cells lacking PDK1. Indeed, disrupting the PDK1 gene in mouse embryonic cells prevents activation of PKB/Akt, p70S6K, and RSK. Williams et al., Current Biology 10, 439-447 (2000). Additionally, in an in vivo model, reducing the expression of PDK1 protects mice from developing tumors under conditions where PIP3 is elevated due to the deletion of PTEN. Bayascas et al., Current Biology 15, 1839-1846 (2005). Thus, while not being bound by any specific theory, inhibiting PDK1 function is expected to mitigate tumor cell proliferation by abrogating cell signaling.
Accordingly, there exists a need in the art for small-molecule inhibitors of PDK1 that are useful for treating cancer and other disorders associated with aberrant PDK1 activity.